Use of a container of an inorganic additive containing plastic material

ABSTRACT

The present invention relates to the use of a container, made of an inorganic additive containing plastic material, for reducing physical/chemical interaction between the container and an oil, fat and/or wax containing formulation contained therein.

FIELD OF THE INVENTION

The present invention relates to the use of a container of an inorganic additive containing plastic material.

DESCRIPTION OF THE RELATED ART

Plastic containers are readily used for pharmaceutical preparations. However it is known that, due to their character, there are some limitations. Thus to suppress the reactivity of containers from polyethylene or polypropylene and their copolymers/blends towards certain chemicals several methods are used: plasticizers are avoided which would increase the motility of the chain molecules, polymers of higher density or polyolefin blends (e.g. polypropylene/polyacrylate) are used, the wall thickness is increased or the containers are wrapped (e.g. aluminium foil) or sealed (e.g. fluorination, silicone).

U.S. Pat. No. 4,123,417 (Finberg, 1978) claims that the toughness of LDPE can be increased by a blend comprising low density polyethylene containing an amorphous ethylene-propylene copolymer having a certain amount of crystallinity and a specified ethylene content.

U.S. Pat. No. 4,546,882 (Hsu et al., 1985) claims a multiple layer package for oil-containing products comprising an oil barrier layer from nylon or ethylene vinyl alcohol.

U.S. Pat. No. 5,500,261 (Takei et al., 1996) claims an oil resistant container comprising a blended resin composition having specified glass-transition temperatures.

U.S. Pat. No. 6,800,363 (Su et al., 2004) claims a film that does not distort in the presence of food oils using a polyolefin multilayer film having a skin layer from oil-absorbing porous particles (calcium carbonate, silicone dioxide, amorphous silica, sodium aluminosilicate, activated charcoal) and a metallized layer.

U.S. Pat. No. 6,815,506 (Takashima et al., 2004) claims an oil-resistant thermoplastic elastomer composition comprising a propylene resin, an unsaturated group-containing acrylic rubber and an inorganic filler for rubber compositions, preferred silica.

Also other additives are usual to improve the properties of plastics. Of high importance are pigments and ultraviolet stabilizers (organic and inorganic pigments, dyes, benzophenone, hindered amines etc.). These cover a broad spectrum of requirements, such as heat stability, fastness to light and weathering, where titanium dioxide (TiO₂) is most common in pharmaceuticals. TiO₂ is an inert substance known for its broad spectrum of UV-absorption and non-migration (movement into the drug formulation).

SUMMARY OF THE INVENTION

It is an object of the invention to provide an alternative use of containers made of an additive containing plastic material, which containers contain an oil, fat and/or wax containing formulation.

This object is achieved by an use of a container, made of an additive containing plastic material, for reducing physical/chemical interaction between the container and an oil, fat and/or wax containing formulation contained therein.

Preferably, the physical/chemical interaction is an adsorption of the formulation to the plastic material.

More preferably, the inorganic additive is at least a pigment.

Most preferably, the at least one pigment is titanium dioxide (TiO₂), surface-treated titanium dioxide, or a mixture thereof.

In one embodiment, the additive is present in the plastic material in an amount between 0.1 and 10% by weight, more preferably between 0.1 and 5% by weight, and most preferably about 2% by weight, based on the weight of the plastic material.

The plastic material may comprises polyolefin.

Preferably, the polyolefin is selected from the group of polyethylene, polypropylene, copolymers of ethylene and propylene, or a mixture thereof.

More preferably, the plastic material comprises low density polyethylene (LDPE).

The plastic material may be suitable for extrusion blow molding.

Preferably, the formulation comprises at least one steroid hormone dissolved or suspended in oil, fat and/or wax.

More preferred, the steroid hormone is a sexual hormone drug, preferably testosterone, and the formulation further comprises at least one lipophilic or partially lipophilic carrier; and a compound or a mixture of compounds having surface tension decreasing activity, in an amount effective for in situ generation of an emulsion upon contact of the formulation with water.

Finally, the formulation is preferably for nasal application, preferably to a mammalian.

A preferred low density polyethylene is for example Lupolen® 1840 H. Further, a preferred formulation may be the one which is disclosed in EP 03025769.5.

Surprisingly, it was found that a container of an inorganic additive containing plastic material may be advantageously utilized for keeping oil, fat and/wax containing formulations, for example oily formulations of steroid hormones, in that the use of such a container will reduce physical-chemical interactions of the container and the formulation, especially the adsorption of the formulation to the plastic material.

Surprisingly, the inventor has found that TiO₂ can also be used for a purpose for which it was not intended to be used so far: By adding it to plastic packaging material the physical-chemical interaction of certain oily formulations with the container, restricting its use, can be prevented.

The approaches actually made dealing with oil—plastic interaction did not use inorganic additive auxiliary agents nor a possibility was described for protecting a corresponding steroid hormone containing formulation from adsorption to plastic.

DETAILED DESCRIPTION OF THE INVENTION

In nasal application forms the suitability of the device for administration is of major importance. This applies to improving patient's compliance by convenient administration. But this also applies to pharmaceutical necessities such as the uniformity of emitted dose and the compatibility of the formulation with the primary packaging material. In pharmaceutical applications it is essential to use inert material for primary packaging; the galenical formulation, the active ingredient and the excipients, should not adversely be influenced by any interaction.

In principle there are two materials and two types for packaging of nasal formulations: glass vs. plastic and multiple-dose vs. unit-dose containers. The main advantages of plastic materials are their flexibility allowing for a wide range of designs, low weight, shatter resistance, and easy handling. Especially suitable for nasal application are unit-dose containers from plastic because of their small size, because no pump mechanism is necessary nor the addition of preservatives to the product formulation.

As starting material for such plastic containers polyethylene or polypropylene and their copolymers are used. Possible drawbacks in respect of their use are the oxygen permeability, poor UV resistance and, due to the nonpolar character, degree of crystallinity and molar mass, the poor resistance to some chemicals.

Thus polyethylene and polypropylene are not generally resistant to aliphatic and aromatic hydrocarbons and their halogen derivatives as well as to low-volatility substances such as fats, oils and waxes. Incompatibilities which can be seen are adsorption of the chemicals to the plastic, diffusion and swelling by the chemicals, or even dissolution in the chemicals.

On the other hand hydrocarbon derivatives such as steroid hormones are readily formulated using oil as carrier to increase their solubility and time of action. To avoid stability problems caused by the primary packaging these oily formulations—mostly injectables—usually are filled into glass devices. This kind of packaging however is not suitable for all application forms, e.g. not for oily formulations for nasal application. In concern of multi-dose devices the reason is that, although the bottle might be from glass, there are always parts of the device, such as the pump, which are from plastic material. In concern of unit-dose devices the reason is that these, at least in the case of viscous formulations which have to be squeezed, cannot be made from glass but moulded from plastics, mostly by the blow-fill-seal technology.

As an example for the aforementioned considerations in table 1 are shown the results of tests investigating the stability of formulations containing the steroid hormone testosterone in containers of different material.

TABLE 1 Stability of formulations containing testosterone in containers of different material Remaining drug Primary packaging material Formulation after storage (%) LDPE Oil-based ≈30% PP Oil-based ≈50% Glass Oil-based ≈80% Glass Methanolic 100% LDPE + TiO₂ Oil-based 100%

The term “remaining drug after storage” is the amount of testosterone remaining in the formulation after storage for 22 hours. The remaining drug was measured by HPLC technique.

It is obvious that there is a complex interaction of the drug with the oily formulation and of the oily formulation with the primary packaging material. For clinical-pharmaceutical reasons however the oil-based formulation and a unit-dose device for packaging was preferred. Thus some effort was made by the applicant using complicated procedures to solve this problem. Surprisingly however after adding titanium dioxide to the plastic material by this simple step it was possible to increase the shelf-life of the pharmaceutical formulation.

The features disclosed in the foregoing description and in the claims may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. 

1.-12. (canceled)
 13. A method for reducing physical/chemical interaction between a container manufactured with a plastic and a lipophilic testosterone nasal gel formulation, comprising the step of: exposing the container to the lipophilic testosterone nasal gel formulation; wherein the plastic comprises an inorganic additive; wherein the lipophilic testosterone nasal gel formulation comprises (i) testosterone, (ii) a lipophilic or partially lipophilic carrier, and (iii) a compound or a mixture of compounds having surface tension decreasing activity; and wherein the lipophilic testosterone gel formulation is used for mammalian nasal application, whereby the physical/chemical interaction between the container and the lipophilic testosterone gel formulation are reduced following said exposure.
 14. The method according to claim 13 wherein the physical/chemical interaction is an adsorption of the formulation to the plastic.
 15. The method according to claim 13, wherein the inorganic additive is at least a pigment.
 16. The method according to claim 15, wherein said pigment is selected from the group consisting of titanium dioxide (TiO₂), surface-treated titanium dioxide, or a mixture thereof.
 17. The method according to claim 13, wherein the additive is present in the plastic in an amount of between about 0.1 and about 10% by weight based on the weight of the plastic.
 18. The method according to claim 13, wherein the plastic comprises polyolefin.
 19. The method according to claim 18, wherein the polyolefin is selected from the group of polyolefins consisting of polyethylene, polypropylene, copolymers of ethylene, propylene and mixtures thereof.
 20. The method according to claim 19, wherein the plastic comprises low density polyethylene (LDPE).
 21. The method according to claim 13, wherein the plastic is suitable for extrusion blow molding.
 22. The method according to claim 13, wherein the additive is present in the plastic in an amount of between about 0.1% to about 5% by weight based on the weight of the plastic material.
 23. The method according to claim 13, wherein the additive is present in the plastic in an amount of about 2% by weight based on the weight of the plastic material.
 24. The method of claim 13, wherein the container extends the shelf life and stability of the lipophilic testosterone gel formulation for a period of time longer than that of a container without the inorganic additive.
 25. A method for reducing physical or chemical interaction between a plastic container and a lipophilic testosterone nasal gel formulation, comprising the steps of: (a) adding to a plastic material comprising polyolefin titanium dioxide (TiO₂) in an amount between about 0.1 and about 10% by weight, based on the weight of the plastic material; and (b) exposing the plastic container to the formulation; wherein the lipophilic testosterone nasal gel formulation comprises (i) at least one steroid hormone dissolved or suspended in a lipophilic or partially lipophilic carrier, and (ii) a compound or a mixture of compounds having surface tension decreasing activity; wherein the formulation is used for mammalian nasal application; and wherein the plastic container extends the shelf life and stability of the lipophilic testosterone nasal gel formulation for a period of time longer than that of a plastic container without the addition of titanium dioxide (TiO₂).
 26. The method according to claim 25, wherein the polyolefin is selected from the group of polyoelfins consisting of polyethylene, polypropylene, copolymers of ethylene, propylene and mixtures thereof.
 27. The method according to 25, wherein the plastic material comprises low density polyethylene (LDPE).
 28. The method according to claim 25, wherein the plastic material is suitable for extrusion blow molding.
 29. The method according to claim 25, wherein the titanium dioxide (TiO₂) is surface-treated titanium dioxide.
 30. The method according to claim 25, wherein the titanium dioxide (TiO₂) is mixed with surface-treated titanium dioxide.
 31. The method according to claim 25, wherein the titanium dioxide (TiO2) is present in the plastic material in an amount of between about 0.1% to about 5% by weight based on the weight of the plastic material.
 32. The method according to claim 25, wherein the titanium dioxide (TiO2) is present in the plastic material in an amount of about 2% by weight based on the weight of the plastic material.
 33. The method according to claim 25, wherein the amount of the testosterone remaining in the lipophilic testosterone nasal gel formulation after long-term storage is about 100%, wherein the percentage of the remaining drug is determined by high performance liquid chromatography (HPLC) technique.
 34. A method for reducing adsorption of a lipophilic testosterone nasal gel formulation into a plastic material used to manufacture a plastic container, comprising the steps of: storing the lipophilic testosterone gel formulation in the plastic container manufactured with the plastic material to reduce adsorption of a lipophilic testosterone nasal gel formulation into the plastic material used to manufacture a plastic container; wherein the plastic material comprises polyolefin titanium dioxide (TiO2) in an amount of between about 0.1 and about 10% by weight, based on the weight of the plastic material; wherein the lipophilic testosterone nasal gel formulation comprises (i) testosterone; (ii) a lipophilic or partially lipophilic carrier, and (ii) a surfactant having surface tension decreasing activity; wherein the lipophilic testosterone nasal gel formulation is applied nasally to a mammalian; and wherein the plastic container extends the shelf life and stability of the lipophilic testosterone nasal gel formulation for a period of time longer than that of a plastic container without the addition of titanium dioxide (TiO₂). 